| Literature DB >> 32424282 |
Alexandra Garancher1, Hiromichi Suzuki2, Svasti Haricharan3, Lianne Q Chau1, Meher Beigi Masihi1, Jessica M Rusert1, Paula S Norris3, Florent Carrette3, Megan M Romero4, Sorana A Morrissy2,5, Patryk Skowron2, Florence M G Cavalli2, Hamza Farooq2, Vijay Ramaswamy6, Steven J M Jones7, Richard A Moore7, Andrew J Mungall7, Yussanne Ma7, Nina Thiessen7, Yisu Li7, Alaide Morcavallo8, Lin Qi9,10, Mari Kogiso9, Yuchen Du9,10, Patricia Baxter9, Jacob J Henderson11, John R Crawford12, Michael L Levy13, James M Olson14, Yoon-Jae Cho11, Aniruddha J Deshpande1, Xiao-Nan Li9,10, Louis Chesler8, Marco A Marra7, Harald Wajant15, Oren J Becher4, Linda M Bradley3, Carl F Ware3, Michael D Taylor2, Robert J Wechsler-Reya16.
Abstract
Many immunotherapies act by enhancing the ability of cytotoxic T cells to kill tumor cells. Killing depends on T cell recognition of antigens presented by class I major histocompatibility complex (MHC-I) proteins on tumor cells. In this study, we showed that medulloblastomas lacking the p53 tumor suppressor do not express surface MHC-I and are therefore resistant to immune rejection. Mechanistically, this is because p53 regulates expression of the peptide transporter Tap1 and the aminopeptidase Erap1, which are required for MHC-I trafficking to the cell surface. In vitro, tumor necrosis factor (TNF) or lymphotoxin-β receptor agonist can rescue expression of Erap1, Tap1 and MHC-I on p53-mutant tumor cells. In vivo, low doses of TNF prolong survival and synergize with immune checkpoint inhibitors to promote tumor rejection. These studies identified p53 as a key regulator of immune evasion and suggest that TNF could be used to enhance sensitivity of tumors to immunotherapy.Entities:
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Year: 2020 PMID： 32424282 PMCID： PMC7456619 DOI： 10.1038/s41593-020-0628-4
Source DB: PubMed Journal: Nat Neurosci ISSN： 1097-6256 Impact factor: 24.884